AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Accelerated Biological Aging Mediates and Healthy Lifestyles Modify Atherosclerotic Cardiovascular Disease Risk Associated with Early Menopause
By Lu Y, Yoshida Y
Background: Women with early menopause are at increased risk of atherosclerotic cardiovascular disease (ASCVD), but the biological pathways underlying this association and the modifying effect of healthy lifestyles remain poorly explored. Hypothesis: We hypothesized that accelerated biological aging mediates the association between early menopause and ASCVD risk, and that healthier lifestyle is associated with lower ASCVD risk among women with early menopause. Methods: We selected the postmenopausal female participants from the UK Biobank, and examined the association between early menopause (age at menopause ≤45 years old) and incident of ASCVD using Cox proportional hazard model, accounting for age, race/ethnicity, history of hormone replacement therapy, total cholesterol, HDL cholesterol, and healthy lifestyle score, which was constructed using four components: smoking, alcohol consumption, physical activity, and body mass index (BMI). Participants received 1 point for each healthy factor: never smoking; moderate alcohol intake (1-3 times per month, 1-2 times per week, or on special occasions only); physically active (≥150 minutes/week of moderate activity or ≥75 minutes/week of vigorous activity); and BMI (18.5-25 kg/m ² ). Scores ranged from 0 to 4, with scores >2 classified as favorable lifestyle). We performed causal mediation analysis to estimate the extent to which biological aging (i.e. PhenoAge acceleration) mediated the association between early menopause and ASCVD. PhenoAge was derived from albumin, creatinine, glucose, C-reactive protein, lymphocyte percentage, mean cell volume, red blood cell distribution width, alkaline phosphatase, and white blood cell count, which positive values indicated biological age acceleration. We evaluated the modifying effect of healthy lifestyle score by adding an interaction term to the full Cox model, followed by a stratified analysis. Results: A total of 28,314 women with early menopause and 114,972 women with normal age menopause were identified. Early menopause was associated with a higher risk of ASCVD (hazard ratio [HR]: 1.21, 95%CI: 1.15-1.27, p<.001). PhenoAge acceleration mediated 10.3% (95%CI: 8.2-12.4%, p<.001) of this association. Among those with favorable lifestyles HR was 1.15 (95%CI: 1.06-1.25), while among those with unfavorable lifestyles, the HR was 1.23 (95%CI: 1.16-1.30) (P-interaction= 0.2). Conclusion: Accelerated biological aging modestly mediates, and a healthier lifestyle significantly modify the ASCVD risk among women with early menopause.